Mercaptopurine prodrug

Saab, A. N Sloan, K. B Beall, H. D and Villanueva, R Effect of aminomethyl (N-Mannich base) derivatization on the ability of S -acctyloxymethyl-6-mercaptopurine prodrug to deliver 6-mercaptopurine through hairless mouse skin. / Pharm. Sci.. 79, 1099,... 

The number of drugs susceptible to S-methylation is still limited but greater than the number turned over by COMT. Thiopurine methyl transferase (TPMT) is an important enzyme responsible for detoxifying mercaptopurine—a drug used to treat leukemia— as well as azathioprine —a prodrug that is metabolized to mercaptopurine (Fig. 7.12). This enzyme is polymorphic and patients who are homozygous for the deficient enzyme experience severe toxicity when given usual doses of mercaptopurine (19). Similar aromatic and heterocyclic sulfhydryls can also be substrates for TPMT. The similar thiol... 

I. Y. Hwang, A. A. Elfarra, Cysteine S-Conjugates May Act as Kidney-Selective Prodrugs Formation of 6-Mercaptopurine by the Renal Metabolism of, V-(6-Purinyl)-i,-cysteine , J. Pharmacol. Exp. Ther. 1989, 251, 448 - 454. 

Azathioprine is a prodrug of mercaptopurine and, like mercaptopurine, functions as an antimetabolite (see Chapter 54). Although its action is presumably mediated by conversion to mercaptopurine and further metabolites, it has been more widely used than mercaptopurine for immunosuppression in humans. These agents represent prototypes of the antimetabolite group of cytotoxic immunosuppressive drugs, and many other agents that kill proliferative cells appear to work at a similar level in the immune response. 

Originally developed for chemotherapy, azathioprine is used today mainly as an immunosuppressive agent and rarely as an antineoplastic drug. It was introduced as an immunosuppressive agent by a British pioneer of tissue transplantation, Roy Caine. Azathioprine was used to prevent rejection after tissue transplantation as a replacement for 6-mercaptopurine because it was less toxic. In addition to tissue transplantation, it is also used for rheumatoid arthritis and Crohn s disease. Azathioprine is a prodrug which in the body is converted to its active metabolites 6-mercaptopurine and 6-thioinosinic acid. Until the discovery of cyclosporine, azathioprine in combination with steroids was the standard treatment to prevent rejection after tissue transplantation. 

Azathioprine is orally absorbed with maximum blood levels attained within 1-2 h. The half-life of the parent drug is 10 min but its metabolite, 6-mercaptopurine, has a half-life of nearly 1 h, and some metabolites have an even longer half-life. The prodrug and the active metabolites both bind to plasma proteins with low affinity and are removed from tissues by oxidation or methylation. 

The second approach to prolonged therapeutic action is based on the controlled rate of conversion of the promoiety into the active compound in vivo. This approach requires particularly detailed study of the kinetics of prodrug-drug conversion. A classic example is bioconversion of azathioprine to 6-mercaptopurine. Azathioprine is used commonly in kidney transplantation, rheumatoid arthritis, and the treatment of various skin disorders. After administration, azathioprine undergoes slow... 

Cytotoxic agents destroy immimologically competent cells. Azathioprine, a prodrug for the purine antagonist mercaptopurine, is used in autoimmune disease because it provides enhanced immunosuppressive activity. Cyclophosphamide is a second choice. Bone marrow is depressed as is to be expected. 

Thiopurines are metabolized by thiopurine methyltransferase, whose activity is controlled by a common genetic polymorphism in the short arm of chromosome 6. Patients with low or intermediate activity who take azathioprine or 6-mercaptopurine are at risk of myelosup-pression caused by excess accumulation of the active thiopurine metabolite 6-thioguanine nucleotide. Benzoic acid derivatives, such as mesalazine and its precursors, and prodrugs (sulfasalazine, olsalazine, and balsalazide) inhibit thiopurine methyltransferase activity in vitro. This action could explain the increase in whole blood concentrations of 6-thioguanine nucleotide, leading to leukopenia. 

Azathioprine, a prodrug converted to 6-mercaptopurine, is widely used as a post-transplant immunosuppressant and in various autoimmune or chronic inflammatory disorders, such as rheumatoid arthritis, dermatomyositis, systemic lupus eiythematosus, skin diseases, and inflammatory bowel diseases. 

Azathioprine, a prodrug for 6-mercaptopurine, has been used as an immunosuppressant in combination with glucocorticoids since the earliest days of the modern transplantat era. It is associated with substantial toxicides, however, and its use has dramatically declined with the availability of newer, less toxic immunosuppressants. 

An interesting example of a DDI due to the inhibition of a non-CYP enzyme that can have serious clinical consequences is the inhibition of xanthine oxidase by allopu-rinol 6-mercaptopurine (6-MP) as an antimetabolite type of antineoplastic drug. One of its indications is in the treatment of inflammatory bowel disease. Actually, 6-MP is a prodrug whose active metabolite, 6-thiogua-nine (6-TG) is responsible for its therapeutic activity. Some nonresponders to 6-MP do not form sufficient amounts of 6-TG. A complementary pathway of 6-MP metabolism is oxidation to 6-thiouric acid (6TU), which is mediated by xanthine oxidase. Inhibition of this complementary pathway by allopurinol shunts the metabolism of 6-MP favoring increased formation of 6-TG. 

Mechanism of action This prodrug is transformed to the anti metabolite mercaptopurine, which upon further metabolic conversion inhibits enzymes involved in purine metabolism. Azathioprine is cytotoxic in the early phase of lymphoid cell proliferation and has a greater effect on the activity of T cells than B cells. 

PO/IV. Prodrug is metabolized to 6-mercaptopurine (6MP). 6MP is converted to 6-thiouric acid by xanthine oxidase. Renal excretion. 

Azathioprine, 6-(l-methyl-4-nitroimidazole-5-yl)-thiopurine, is a prodrug that is converted non-enzymatically to mercaptopurine (Figure 1) and subsequently to thioguanine nucleotides. It is therefore not unexpected... 

---